Technical Field
The invention relates to furo-3-carboxamides that are inhibitors of TrkA (Tropomyosin receptor kinase isoform A), useful in treating diseases and conditions mediated and modulated by TrkA. Additionally, the invention relates to compositions containing compounds of the invention and processes of their preparation.
Description of Related Technology
TrkA is member of the Trk (Tropomyosin receptor) receptor family. Currently this family is known to include three highly homologous isoforms, called TrkA, TrkB, and TrkC. Trk receptors (Trks) are high affinity receptor tyrosine kinases. Trks bind adenosine triphosphate (ATP) and modulate intracellular signaling through their kinase enzymatic activity which is able to phosphorylate specific tyrosine residues of target proteins and peptides. Each Trk receptor isoform can be activated by endogenous peptidic factors known as neurotrophins (NT), which act as agonists of the Trk receptor. NGF (nerve growth factor) is a high affinity activator of TrkA. BDNF (brain-derived neurotrophic factor) and NT-4/5 are high affinity activators of TrkB (Tropomyosin receptor kinase isoform B). NT3 is a high affinity activator of TrkC (Tropomyosin receptor kinase isoform C). Trks are expressed in neurons, and have been implicated in the development and function of the nervous system, as well as other physiological processes.
Neurotrophins and their Trk receptors have been implicated in pain sensation and in inflammation. Pezet S, et al. Ann Rev Neuroscience 2006; 29:507-538; Mantyh P W, et al. Anesthesiology 2011; 115:189-204; and Patapoutian A, et al. Current Opinion in Neurobiology 2001; 11:272-280. Studies have shown that NGF, the agonist of TrkA, modulates pain in adult mammals. Dyck P J, et al. Neurology 1997; 48; 501-505; and Deising S, et al. Pain 2012; 153:1673-1679. Studies have also shown that inhibitors of the NGF/TrkA pathway are effective in blocking pain. Lane N E, et al. New England J Med 2010; 363:1521-1531; Schnitzer T J, et al. Osteoarthritis Cartilage 2011; 19:639-646; Katz N, et al. Pain 2011; 152:2248-2258; Evans R J, et al. J. Urology 2011; 185:1716-1721; Shelton D L, et al. Pain 2005; 116:8-16; Ro L S, et al. Pain 1999; 79:265-274; and Ugolini G, et al. Proceedings of the National Academy of Sciences of the USA 2007; 104:2985-2990. TrkA inhibitors block NGF signaling through its receptor (TrkA) and have been found effective in reducing pain in animal models. Ghilardi J R, et al. Bone 2011; 48:389-298; Ghilardi J R, et al. Molecular Pain 2010; 6:87; Mantyh, W G, et al, Neuroscience 2010; 17:588-598; and Hayashi K, et al. Journal of Pain 2011; 12:1059-1068. The TrkA, TrkB, and TrkC isoforms have high structural homology. Of the potent Trk inhibitor structural classes described, testing of isoform selectivity has revealed a lack of selectivity for any particular Trk isoform, hence they have been termed ‘pan-Trk’ inhibitors (Albaugh P, et al. ACS Medicinal Chemistry Letters 2012; 3:140-145), able to inhibit TrkA, TrkB, and TrkC. Wang T, et al. Expert Opinion on Therapeutic Patents 2009; 19:305-319.
Although compounds and mechanisms exist that are used clinically to treat pain, there is need for new compounds that can effectively treat different types of pain. Pain of various types (e.g., inflammatory pain, post-surgical pain, osteoarthritis pain, neuropathic pain) afflicts virtually all humans and animals at one time or another, and a substantial number of medical disorders and conditions produce some sort of pain as a prominent concern requiring treatment. As such, it would be particularly beneficial to identify new compounds for treating the various types of pain.